Background: Disability resulting from stroke and traumatic brain injury represent the main cause of long-term disability among adults. There are no universally accepted treatments available for the treatment of this condition and the financial, personal, familiar and social cost of this disability cannot be underestimated. Preliminary data from different laboratories has shown that it is possible to modulate plastic processes in the lesioned brain by pharmacological, brain stimulation and somatosensory stimulation techniques. The purpose of this Z01 is to identify mechanisms of stroke motor disability and characterize the most promising techniques to improve cortical plasticity in these patients in order to enhance functional recovery. Findings this year: From a pathophysiological point of view, we found in cerebellar stroke patients that short intracortical inhibition (SICI) was decreased in the contralesional primary motor cortex compared to ipsilesional M1 in the absence of side-to-side differences in healthy controls. These results document disinhibition of contralesional M1 in the chronic phase after cerebellar stroke. In patients with subcortical strokes (not involving the cerebellum), we found an abnormal persistence of SICI in the ipsilesional M1 during movement preparation that was absent in age-matched controls. Additionally, resting SICI was reduced in the patient group relative to controls. Alltogether, these findings document deficient premovement modulation of intracortical inhibition in the ipsilesional M1 of patients with chronic stroke, an abnormality that might contribute to deficits in motor control of the paretic hand. We also investigated the neurophysiological mechanisms underlying training-dependent improvements in upper-extremity motor skills in stroke patients with substantial motor disability, the majority of stroke survivors. Preceding training, we found greater interhemispheric inhibition (measured by ipsilateral silent periods) in the affected triceps muscle, reflecting inhibition from the nonlesioned to the lesioned primary motor cortex in patients with more severe motor impairment. Training-induced improvements in reaching were greater in patients with slower response times at baseline. Increased motor evoked potential amplitudes and decreased silent periods were observed in the affected triceps but not in the biceps muscle after training. These results indicate that along with training-induced motor improvements, training-specific modulation of intrahemispheric and interhemispheric mechanisms occurs after reaching practice in chronic stroke patients with substantial arm impairment. We collaborated in an investigation on metabolites studied with MR spectroscopy in the primary motor cortex after stroke. It was shown that stroke survivors showed lower N-acetylaspartate and higher myo-inositol across ipsilesional and contralesional M1 compared with control subjects. Significant correlations between N-acetylaspartate and glutamate/glutamine were found in M1. Ipsilesional N-acetylaspartate and glutamate/glutamine were positively correlated with arm motor impairment and contralesional N-acetylaspartate with time after stroke. The results were interpreted as preliminary, suggesting significant alterations of neuronal-glial interactions in spared M1 with the ipsilesional alterations related to stroke severity and contralesional alterations to stroke duration. We have also implemented interventional trials in stroke patients. We participated in the first randomized parallel controlled trial assessing the feasibility, safety, and efficacy of virtual reality using Wii gaming technology in stroke rehabilitation and the results may serve as the basis for a larger multicentre trial. We determined that application of multiple sessions of somatosensory stimulation to the paretic limb could facilitate training effects on motor function after subacute stroke depending on the intensity of stimulation. It was proposed that careful dose-response studies are needed to optimize parameters of somatosensory stimulation before designing costly, larger double-blind multicenter clinical trials. All together we advanced our understanding of the mechanisms underlying motor stroke disability and in the development of interventions that could facilitate functional recovery after chronic stroke.